In the treatment of neoplasia, such as solid tumors in the early stages, surgical excision or ablation with radiation often provides a successful form of therapy. However, this is not the case for many solid tumors that have advanced to later stages. Locally advanced or locally invasive solid tumors are primary cancers that have extensively invaded or infiltrated into the otherwise healthy tissues surrounding the site where the tumor originated. Locally advanced tumors may arise in tissues throughout the body, but unlike early stage tumors may not be amenable to complete surgical excision or complete ablation using radiation treatments. Due to the invasion of the surrounding tissues by tumor processes, any surgical procedure that would serve to remove all the cancerous cells would also be likely to maim or destroy the organ in which the cancer originated. Similarly, radiation treatments intended to eradicate the cancerous cells left behind following surgery frequently lead to severe and irreparable damage to the tissues in and around the intended treatment field. Often, surgery is combined with radiotherapy, chemotherapy or a combination of adjuvant therapies designed to eliminate the malignant cells that could not be removed by the surgery. However, when a tumor has infiltrated into otherwise healthy tissues surrounding the site where the tumor originated, even combination treatments including surgery plus radiation therapy, or surgery plus radiation therapy plus chemotherapy may not be capable of eradicating the tumor cells without causing severe damage to the tissues in the treatment field. Neither surgeons nor radiotherapists have the tools to eliminate individual tumor cells, microscopic tumor processes, or tumor-associated vasculature from the otherwise normal tissue surrounding locally advanced solid tumors. Nevertheless, in the interest of preserving the overall structure of tissues being invaded by cancer cells, conventional radiation therapy is widely used in the treatment of locally advanced solid tumors.
Conventional radiation therapy involves the exposure of cancerous tissues to megavoltage x-ray beams (i.e. gamma photons) and is a well-established anti-cancer treatment modality. Conventional radiation therapy is curative for selected early stage tumors, and is the treatment of choice to mitigate the symptoms of locally advanced solid tumors and selected metastatic tumors. Conventional radiation therapy can be administered using quantitative and reproducible treatment protocols, and x-rays are synergistic when administered with certain cytotoxic drugs and biological agents. Conventional radiation therapy is an effective anticancer treatment that is used to treat tumors throughout the body.
Despite the above mentioned benefits, and its widespread use, conventional radiation therapy cannot cure locally advanced solid tumors, because, in order to gain access to a tumor mass, x-ray beams usually must pass completely through the body; therefore, exposure to normal tissues is inevitable. In addition, x-ray beams lack the microscopic accuracy needed to eliminate individual cancer cells from the treatment field. X-rays cannot eradicate or cure most types of locally advanced solid tumors, because they lack the specificity needed to kill cancer cells while sparing the normal cells in the treatment field.
Notwithstanding the macroscopic scale of x-ray beams, the increased accuracy of radiotherapy beams is recognized to improve the clinical benefit-to-risk ratio. Indeed, digital imaging technologies are used to help radiotherapists with pre-treatment planning. For example, CT and MRI are used to map the 3-D contours of solid tumors, and thereby define a “treatment field” to be irradiated with x-rays. The goal is to irradiate tumors with a wide variety of 3-D shapes while avoiding the tissues surrounding the treatment field. Unfortunately, this approach is of limited value even in instances when the x-ray beam can be focused precisely on the treatment field. The main problem is that x-rays cannot discriminate between the cancer cells and normal cells within the treatment field. Because of this conventional radiation is associated with side effects, often severe, including mucositis, alopecia, dermatitis, proctitis, enteritis, and tissue necrosis. Brain tissue is particularly sensitive to the toxic effects of ionizing radiation. Radiotoxic effects in the CNS include cognitive impairments, inflammation of the white matter and full blown inflammatory brain necrosis.
Regardless of how precisely one defines the treatment field, and regardless of how precisely the x-ray beam is projected through the treatment field, x-rays will damage normal cells in the treatment field, and radiotherapy beams do not have the microscopic accuracy needed to eliminate individual cancer cells from the treatment field. Thus, even the most precise digital pre-treatment planning cannot overcome the inherent deficiencies of ionizing radiation.
Even using a combination of systemic agents and conventional radiation, nearly one third of patients with locally advanced solid tumors relapse (Vijaykumar, S. and Hellman, S., “Advances in Radiation Oncology,” Lancet, 349[S11]: 1-3 (1997)). Most types of chemotherapy also suffer from a lack of tumor specificity and also cause collateral damage to normal tissues, since chemotherapeutic agents are distributed throughout the body and exert their effects on normal cells as well as malignant cells. Many systemic chemotherapy agents act on cells undergoing DNA synthesis and cell division, and thus may impact many cell populations throughout the body in addition to the target cancer cells.
The deficiencies of current treatment modalities are especially glaring with respect to specific types of cancer, for example glioblastoma multiforme (GBM), a highly aggressive type of cancer that constitutes the most common form of brain malignancy. Indeed, after nearly 35 years of investigations involving hundreds of experimental treatments and thousands of GBM patients participating in clinical trials, the prognosis of patients with newly diagnosed GBM is dismal. In a recent survey, the survival following the diagnosis of GBM is only 42% at 6 months, 18% at one year, and 3% at 2 years (Ohgaki, et al., “Genetic pathways to glioblastoma: A population-based study,” Cancer Research, 64:6892-6899 (2004)).
The currently favored treatment for newly diagnosed GBM is surgical resection followed by a course of ionizing radiation plus oral temozolomide, a chemotherapy agent that is administered during and after the course of radiation. In patients receiving this treatment, the best currently available, the median prolongation pf survival is only about 2-3 months beyond surgery and radiation alone.
Recently, techniques have been developed to increase the effective concentration of chemotherapeutic agents at a tumor site. In the treatment of GBM, interstitial or localized chemotherapy has been used with modest success. Wafers containing carmustine (a chemotherapy agent) are inserted into the cavity created by surgical removal of the tumor. The wafers release carmustine into the brain tissue in the immediate vicinity of the brain tumor. This treatment has been shown to increase the median survival from 11.6 months to 13.9 months in patients also treated with surgery and radiation beam therapy (Westphal, M., et al., “A phase III trial of local chemotherapy with biodegradable carmustine (BCNU) wafers in patients with primary malignant glioma,” Neuro-oncology, 5:79-88 (2003)). Interstitial treatments may be particularly well suited for treatment of GBM, as greater than 90% of GBM tumors that recur following surgical resection are localized within 2 cm of the surgical margin (Hochberg, F. H., and Pruitt, A., Neurology, 30:907-911 (1980)). Localizing the concentration of a chemotherapeutic agent by physical techniques (as distinct from biochemical targeting) seems to offer certain advantages compared to systemic chemotherapy. However, the challenge is great, because the majority of chemical entities do not diffuse far into brain tissue or other types of solid tissues.
Another development in physically localized delivery of anticancer agents is convection enhanced delivery. In this technique, a fluid is delivered directly to the cancerous tissues and not through the circulatory system. The fluid is applied under sustained pressure such that the liquid moves by the forces of bulk flow through the interstices of the tissue, carrying with it any dissolved materials. Convection enhanced delivery also bypasses the blood-brain barrier in brain tissue. For example, see Bobo, R. H., et al., “Convection-enhanced delivery of macromolecules in the brain,” Proc. Nat. Acad. Sci. USA, 91: 2076-2080 (1994); Laske, D W. et al. “Convection-enhanced drug delivery,” U.S. Pat. No. 5,720,720 (Feb. 24, 1998); Raghavan, R. et al., “Convection-Enhanced Delivery of Therapeutics for Brain Disease, and Its Optimization,” Neurosurgery Focus 20(4):E12 (2006); and Hall, W. A., et. al,. “Convection-enhanced delivery in clinical trials,” Neurosurgery Focus 14, 1-4, (2003). By comparison to diffusion-based local drug delivery, convection-enhanced delivery serves to increase the effective distance over which a bioactive agent can be delivered into solid tissues. Bulk flow or convection-enhancement of treatment fluid results from the application of a sustained pressure as needed to generate flow rates of at least 0.5 microliters per minute from each catheter tip implanted into the cerebral tissue. For example, see Bobo, R. H., et al., “Convection-enhanced delivery of macromolecules in the brain,” Proc. Nat. Acad. Sci. USA, 91: 2076-2080 (1994); Laske, D W. et al. “Convection-enhanced drug delivery,” U.S. Pat. No. 5,720,720 (Feb. 24, 1998); The flow rates required to generate bulk flow in various other tissues, such as specific types of cancerous tissues, have not been determined.
Convection enhanced delivery has been used with modest success to deliver a number of bioactive agents, mostly proteins, into cerebral tissues of patients with malignant brain tumors. Convection enhanced delivery usually involves 2-4 catheters that are inserted such that the catheter tips are located at selected positions in the vicinity of the surgical resection cavity. The catheters are often inserted one at a time and from multiple points of origin on the outer surface of the brain.
Currently available methods of convection enhanced delivery have several limitations and drawbacks. One of the biggest problems is to determine the optimal position of the catheter tips. This is important not only to ensure that the infusate gains access to the entire intended treatment field, but also to minimize exposure to uninvolved regions of the brain. Optimal catheter placement is especially challenging given the highly variable size and shape of surgical resection cavities. There is also substantial variation in the anatomy and fluid convection dynamics in the cerebral tissues, i.e. white matter tracts provide more rapid and linear convective flow than gray matter. Regional differences in anatomy and fluid dynamics increase the challenge of accurate catheter placement. Another problem that aggravates the optimal positioning of catheter tips is tissue swelling. Cerebral tissues tend to shift their position during the early postoperative period as tissue edema resolves. This makes it quite difficult to accurately position the tips of catheters into the perimeter of the surgical resection cavity. To address this issue, surgeons may wait up to a week after the initial brain tumor operation, when swelling has diminished, to insert the catheters.
Convection enhanced delivery, as currently applied to the treatment of human brain tumors, employs relatively thick catheters with at least a 2.5 mm outer diameter. Such catheters provide relatively low resistance to backflow around the outer wall of the catheter as compared to smaller catheters. Thick catheters must be advanced at least a couple of centimeters into the cerebral tissue in order to provide an adequate seal needed to stop or minimize backflow. This requirement has prompted surgeons to insert such catheters from multiple points on the surface of the brain. The surgeon may inserts such catheters from points of entry within the sulci, i.e. the gaps between the spaghetti-like gyri on the surface of the brain. Insertion of such thick catheters from inside of the surgical resection cavity is challenging because of the minimum depth requirement, by their limited pliability, and by their sheer bulk. The use of 2.5 mm OD catheters may increase the risk of hemorrhage and/or trauma to nervous tissues as compared with thinner catheters. Given the above constraints it is very difficult to consistently arrange the tips of thick catheters into an orderly distribution around many surgical resection cavities.
Another limiting factor is that each catheter supplies a large proportion of the intended treatment field, e.g. 33% of the treatment field for 3 catheters, and 50% of the treatment field for 2 catheters. A high proportional flow per catheter is an unavoidable consequence of using only a few catheters, and has the effect of reducing the accuracy of convection enhanced delivery. Suboptimal placement of a single catheter tip can markedly affect the overall pattern of biodistribution. In addition, the use of a high fractional flow per catheter, and the fact that the catheters must be inserted from the surface of the brain, limits the surgeon's available options for catheter insertion.
Based upon clinical experience from many convection enhanced delivery studies involving patients with brain tumors, 2-3 catheters appear to be insufficient to provide optimal biodistribution of drugs around many surgical resection cavities.
The effective treatment of locally advanced solid tumors, including GBM, requires not only improved methods of drug delivery, but also therapeutic agents capable of eliminating the cancer cells while at the same time sparing normal tissues that have been invaded by the cancer cells. In this regard, a major issue revealed by studies of gene expression profiling, is that tumors are genetically and metabolically much more heterogeneous than previously anticipated. Tumors may be genetically and metabolically heterogeneous despite a common organ or tissue of origin, and despite a very similar appearance under the microscope. This is especially true of GBM and other malignant gliomas that arise in the central nervous system. For example, see H. S. Phillips et al., “Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis,” Cancer Cell 9, 157-173 [2006]; and P.S. Mischel et al., “DNA-Microarray Analysis of Brain Cancer: Molecular Classification for Therapy,” Nature Cancer Reviews, 5:782-792 (2004). In view of the tumor heterogeneity, biochemical targeting, i.e. the search for agents that specifically target each tumor type, is a daunting challenge.
New and effective treatments are needed to eliminate tumor cells with a wide range of genetic and metabolic profiles; to eliminate tumor stem cells, which have the capacity for self-renewal, unlimited proliferative potential, and an inherent resistance to chemotherapy and ionizing radiation; and to minimize or avoid toxicity to normal cells and tissues both inside and outside of the treatment field. One approach to this problem is physically localized delivery of an agent capable of killing many different types of cancer cells, while at the same time having minimal or no toxicity to normal cells within the treatment field. This approach is distinct from the concept of targeted therapy, in which a different drug mechanism may be needed to treat each tumor according to its distinct genetic and metabolic profile.
A unique cell killing mechanism that has garnered considerable interest is the release of Auger electrons. These electrons are emitted by radionuclides that decay by electron capture and internal conversion. Examples of Auger emitting radionuclides include 123Iodine, 125Iodine, 77Bromine and 80mBromine. Auger electrons have energies even lower than the energy of the beta particle emitted by tritium. This effect is amplified, because some Auger emitters release multiple electrons with each nuclear transformation. The low energy of the Auger electrons results in extremely short particle path lengths within tissues, which is highly desirable, because it minimizes collateral damage.
One molecular entity incorporating 125I is [125I]-iodouridine-deoxyriboside (125IUDR), a thymidine analogue. 125IUDR is recognized by DNA polymerases as thymidine, and thus is incorporated into the chromosomes at times of DNA synthesis. Once incorporated into the DNA, the Auger electrons, with their very short range, have access to the chemical backbone of the DNA double helix. When the 125I atom disintegrates, Auger electrons cause irreparable destruction of the chromosomes within the target cell, but with minimal effect on cells in the immediate vicinity of the target cell. 125IUDR and related compounds destroy cells that make DNA, but have little or no effect on other cells.
Despite the recognition that 125IUDR has a unique cell killing capability, and despite many years of research aimed at exploiting this mechanism of action, including the concept of directly introducing 125IUDR into tumors (for example, see Kassis et. al., “Treatment of tumors with 5-radioiodo-2′-deoxyuridine,” U.S. Pat. No. 5,077,034), these agents have not been successfully applied to the treatment of cancer. The delivery of 125IUDR and related agents to solid tumors, using systemic or local administration, has proven to be extremely challenging.
There is a need for new devices and methods of use aimed at exploiting the unique mechanism of action of 125IUDR, 123IUDR and related compounds. New approaches are needed to deliver 125IUDR (and other compounds) to solid tumors with the intent to eliminate cycling tumor cells, including the tumor-maintaining stem cells and their progenitors, while at the same time sparing normal tissues that have been invaded by the cancer cells. This need includes methods for delivery of such agents directly into the tumors and into the normal tissues that have been invaded by tumor cells, particularly in away that provides for substantially uniform treatment of an often-irregularly shaped volume of tissue.